This invention relates to crosslinked hydrophilic polymers which are suitable for use as a carrier for medicaments and other active ingredients; as hydrophilic membranes for separation processes; bandages for wound treatments; body implants; e.g., artificial veins and coatings on glass, metal, wood or ceramics, and in particular, for use in applications where strength of the polymer article and high permeability to water and oxygen are required simultaneously, as in contact lenses.
Hydrogels have been described since 1956 (U.S. Pat. No. 2,976,576) and subsequently a large number of patents have been issued describing the synthesis and use of hydrogels based primarily on 2-hydroxyethyl methacrylate and, to a lesser extent, on N-vinylpyrrolidone. Typically, these hydrogels are crosslinked, water-swellable polymers made by copolymerization of 2-hydroxyethyl methacrylate. They are used as polymeric, inert carriers for active substances, which are slowly and controllably released from these carriers; such active substances may be drugs (U.S. Pat. Nos. 3,574,826; 3,577,512; 3,551,556; 3,520,949; 3,576,760; 3,641,237; 3,660,563); agricultural chemicals (U.S. Pat. Nos. 3,576,760); or fragrances (3,567,118; 3, 697,643).
Their uses as antifogging coatings (U.S. Pat. No. 3,488,215), body implants and bandages have also been described in U.S. Pat. Nos. 3,577,516; 3,695,921; 3,512,183; 3,674,901. The widely used soft contact lens consists of this material (U.S. Pat. Nos. 3,488,111; 3,660,545;).
In the pharmaceutical field the main interest lies in the slow and controllable release of drugs from such hydrogels. Drug-containing hydrogel preparations have been described as being in the form of bandages; subcutaneous implants; buccal devices, intrauterine devices, and eye inserts. They are made by complicated fabrication procedures which usually involves casting the monomer solution into a suitable mold and polymerizing in the presence of a free radical generating initiator.
The use of drug loaded hydrogel granules as an oral dose form has also been suggested (U.S. Pat. No. 3,551,556). It is indeed one of the most useful applications of this concept in medicine since it allows the delivery into the bloodstream of an orally taken drug to spread out over several hours in a reproducible manner. This eliminates wasteful and potentially dangerous peak drug concentrations in the blood, while prolonging the time during which preferred and effective drug levels in the blood are maintained.
Sparingly crosslinked, water-insoluble, hydrophilic polymers are known which are made by the copolymerization of a major amount of a hydrophilic monoolefinic monomer and a minor amount, ranging from 0.01 to 15% of said monoolefin, of a low molecular weight crosslinking agent.
These hydrophilic monoolefinic monomers are generally the monoesters of acrylic or methacrylic acid with polyfunctional alcohols. 2-Hydroxyethyl methacrylate is particularly widely used. The crosslinking agents are generally the diesters of the same acids with the same polyfunctional alcohols, and ethylene bis-methacrylate is particularly widely used.
The copolymerization is carried out in the presence of water (U.S. Pat. No. 3,220,960) or in a water-free system (U.S. Pat. No. 3,520,949). Low molecular weight as well as macromolecular, water-soluble substances, such as poly(ethylene oxide) monomethacrylate together with a minor amount of the corresponding bis-methacrylate have been used (U.S. Pat. No. 3,220,960) as monomers and crosslinking agents. The water-soluble, but hydrophilic copolymers and the process for their production have been modified in several directions and adapted to specific purposes, e.g., the production of soft contact lenses (U.S. Pat. No. 3,220,960 and Reissue No. 27,401), and the copolymerization in the presence of a linear polyamide resin in order to improve or modify the mechanical properties of shaped bodies formed from the polymers obtained (U.S. Pat. No. 3,520,949). However, in all modifications low molecular weight polyolefinic crosslinking agents, especially ethylene bis-methacrylate, were used in very small to moderate amounts never exceeding 20% of the amount of the monoolefinic monomer. Though the copolymers of the type described above could be modified to comply with the requirements of several different methods of using them, the mechanical properties in either the unswollen, i.e., water-free, or the swollen, i.e., equilibrium state with water, could not be satisfactorily adapted to meet all enduse requirements. It is known that hydrophilic polymers whose major constituents are monoesters of acrylic acid and methacrylic acid and a bifunctional alcohol (glycol) have glass transition temperatures or softening points between 55.degree. C. and 80.degree. C. For this reason said prior art articles are brittle and glassy in the dry state at temperatures below 55.degree. C. After equilibration in water these prior art articles become soft and somewhat pliable, but also weak with respect to their flexural properties. In addition, said prior art articles are very susceptible to tearing shear forces if they are inadvertently damaged in any way. Specifically they are extremely friable in the swollen state.
In order to avoid the undesirable weak characteristics of articles produced by said prior art polymers, a medium made of a stronger polymeric material is used as a physical support, or the pre-polymerized mixture is filled with an insoluble material such as silica gel. These techniques, although they afford a certain amount of cohesive strength (the hydrogel material acting as a glue), produce articles which are still susceptible to glassy fracture in the dry state, and shear fracture in the swollen state within the interstitial regions of the article. By the same token, addition of fillers to the prepolymer modify the diffusion properties and water permeability of the article often in unacceptable manner. Of course, an opaque polymer cannot be used as a contact lens material.
Copending application Ser. No. 581,065, filed May 27, 1975 and now abandoned, describes a new class of hydrogel materials, which do not show these drawbacks, but are tough and flexible in the dry as well as in the swollen state. This is achieved by incorporation of a major amount of a hydrophobic high-molecular weight crosslinking agent, which gives macromeric, flexible crosslinks rather than the conventional short crosslinks, which lead to brittleness. Still, for many applications the oxygen permeability was too low, especially for compositions of low equilibrium water content. The combination of a low, but appreciable water content and high oxygen permeability is especially important in the soft-contact lens field; contact lenses should be high enough in water content to make wearing them comfortable, but not too high as to lead to optical distortions. On the other hand, they should show high oxygen permeability at these low degrees of swelling. At the same time they should be tough and flexible and yet suitable for machining and polishing.
It has long been known that silicone based polymers have high oxygen permeability and silicone based contact lenses have been described in British Pat. No. 1,170,810 and French Pat. No. 1,526,934 as well as German Offen. No. 2,228,180. In all these cases a silicone polymer forms the core of a contact lens, whose surface has to be specially treated in order to render it hydrophilic and compatible with the cornea of the eye. This is achieved by grafting a hydrophilic monomer onto the contact lens using free radicals generating radiation in the presence or absence of oxygen. This can be done either during or after fabrication of the contact lens, but in either case it is a complicated process and difficult to control. Diffusion of the monomer into the core has to be prevented because it leads to cloudiness and each lens has to be molded separately and because the soft and friable polysiloxane core cannot be machined. The ability to machine and polish a contact lens out of a small blank is a great advantage because it allows one to adjust the lens to individual needs with great precision.
It has now been discovered, that an unexpectedly ideal combination of useful properties can be obtained by synthesizing a hydrogel containing a major proportion of a polymeric polysiloxane based crosslinking agent. This combination of properties includes: hydrophilicity; oxygen permeability; flexibility and toughness in the dry and swollen state; biocompatibility; polishability and machinability in general; clarity; ease and economy of synthesis.